VER-155008

VER-155008 is an inhibitor of Hsp70, with IC50s of 0.5 μM, 2.6 μM, and 2.6 μM for Hsp70, Hsc70 and Grp7, respectively, and with a Kd of 0.3 μM for Hsp70.

Signaling Pathways >> Autophagy >> Autophagy

Signaling Pathways >> Cell Cycle/DNA Damage >> HSP

Signaling Pathways >> Metabolic Enzyme/Protease >> HSP

Research Areas >> Neurological Disease

HSP70:0.5 μM (IC50)

HSC70:2.6 μM (IC50)

Grp78:2.6 μM (IC50)

VER-155008 is an inhibitor of Hsc70 and Hsp70, with IC50s of 0.5 μM, 2.6 μM, and 2.6 μM for Hsp70, Hsc70 and Grp7, respectively, a with a Kd of 0.3 μM for Hsp70, but shows no activities against Hsp90, with an IC50 of >200 μM. VER-155008 inhibits the proliferation of a variety of human colon and breast tumor cell lines, such as BT474, MB-468, HCT116 and HT29 cells, with GI50s of 10.4 μM, 14.4 μM, 5.3 μM, and 12.8 μM, respectively. VER-155008 (5-40 μM) induces client protein degradation in HCT116 and BT474 carcinoma cells. VER-155008 also induces apoptosis in human tumor cell lines[1]. VER-155008 (0.05-5 μM) reverses Aβ-induced axonal degeneration in cultured neurons[2]. VER-155008 (10 μM or 25 μM) inhibits Hsp70 and suppresses the proliferation of LNCaP95 cells. VER-155008 also reduces full-length androgen receptor (AR-FL) and androgen receptor splice variant 7 (AR-V7) protein expression[3].

VER-155008 (25 mg/kg, i.v.) exhibits plasma clearance in naive female BALB/c mice. VER-155008 (40 mg/kg, i.v.) also shows rapid plasma clearance, and reduces the tumor levels in the HCT116 tumor bearing nude BALB/c mice[1]. VER-155008 (10 μmol/kg/day, i.p.) rescues memory deficits, and reduces axonal swelling associated with amyloid plaques in 5XFAD mice. VER-155008 (89.9 μmol/kg/day, i.p.) penetrates into the brain after administration in 5XFAD mice. VER-155008 also decreases amyloid plaques and PHF-tau associated with amyloid plaques in 5XFAD mice[2].

Embryos are removed from a pregnant ddY mouse at 14 days of gestation. Cells are treated with or without 10 μM Aβ25-35 for 3 days, followed by the addition of 0.05, 0.5, or 5 μM VER-155008 or vehicle solution (0.1% DMSO) for 4 days. The Aβ25-35 is incubated at 37°C for 4 days prior to treatment to facilitate aggregation. The cells are fixed with 4% paraformaldehyde and immunostained at 4°C for 24 h with antibodies against the axonal marker, mouse phosphorylated neurofilament heavy subunit, and against the neuronal marker, rabbit microtubule-associated protein 2. Alexa Fluor 488-conjugated goat anti-mouse IgG (1:400) and Alexa Fluor 568-conjugated goat anti-rabbit IgG (1:400) are used as secondary antibodies. Fluorescence images (864.98 μm × 645.62 μm) are captured using a fluorescence microscopy system. The lengths of the pNF-H-positive axons are measured using MetaMorph version 7.8[2].

Female BALB/c mice are dosed intravenously with 25 mg/kg VER-155008 into the lateral tail vein as a solution in 10% DMSO/5% Tween 80/85% saline (v/v/v). Animals are sacrificed at 5, 15 and 30 min, 1, 2, 4 and 6 h post dose[1].

[1]. Massey AJ, et al. A novel, small molecule inhibitor of Hsc70/Hsp70 potentiates Hsp90 inhibitor induced apoptosis in HCT116 colon carcinoma cells. Cancer Chemother Pharmacol. 2010 Aug;66(3):535-45.

[2]. Yang X, et al. Heat Shock Cognate 70 Inhibitor, VER-155008, Reduces Memory Deficits and Axonal Degeneration in a Mouse Model of Alzheimer's Disease. Front Pharmacol. 2018 Jan 30;9:48.

[3]. Kita K, et al. Heat shock protein 70 inhibitors suppress androgen receptor expression in LNCaP95 prostate cancer cells. Cancer Sci. 2017 Sep;108(9):1820-1827.

17-AAG | Ganetespib(STA-9090) | NVP-AUY922 | Geldanamycin | AT13387 | 17-DMAG (Alvespimycin) HCl | BIIB021 | Apoptozole | IPI-504 | KNK437 | Teprenone | KRIBB11 | Debio-0932 | HSP-990 | PU-H71